Central Nervous System Involvement in a Case of Familial Hemophagocytic Lymphohistiocytosis with Perforin Mutation

Summary: Central nervous system involvement in a case of familial hemophagocylic lymphohistiocytosis with perforin mutation: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive lethal condition characterized by fever, cytopenia, hepatosplenomegaly and hemophagocytosis. The presence of central nervous system involvement has a profound impact on the prognosis, treatment, and clinical outcome of the disease. Therefore, the identification of the clinical manifestations of the disease and the characterization of the accompanying neurological symptoms are of prime importance for the rapid diagnosis and subsequent clinical management of the disease. Herein, we report a case of FHL with homozygosity for perforin gene mutation, who presented with central nervous system involvement in the absence of systemic findings.

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive immune system disorder. Disease-causing mutations in the perforin (PRFl; also known as FHL2), Muncl3-4 (UNC13D; also known as FHL3), syntaxin-11 (STXIl; also known as FHL4) and syntaxin-binding protein 2 (Muncl8-2; also known as FHLS) genes have been identified in individuals with FHL (2, 8, 1 1). It is characterized by persistent fever, moderate to massive hepatosplenomegaly, cytopenia, hypertriglyceridemia, hyperferritinemia and/or hypofibrinogenemia, and variable degree in hemophagocytosis in the bone marrow, cerebrospinal fluid or lymph nodes and mainly affecting infants and young children (8, 14). In addition, many of the patients develop progressive cerebromeningeal symptoms during the course of the disease (17). Cerebromeningeal symptoms are extremely variable, ranging from irritability and neck stiffness, to convulsions, cranial nerve palsies, ataxia, hemiplegia/ tetraplegia, and unconsciousness (9). The presence of central nervous system (CNS) involvement has a profound impact on the prognosis, treatment, and clinical outcome of the disease. Therefore, the identification of the clinical manifestations of the disease and the characterization of the accompanying neurological symptoms are of prime importance for the rapid diagnosis and subsequent clinical management of the disease (4). Stepp et al. (18) identified mutations in the perforin gene in FHL patients linked to chromosome 1 0, which was later found to be responsible for approximately 20-40 % of the FHL cases (3). The symptoms are caused by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines (14).

Previously, we reported the pathologic sequence changes and associated clinical phenotypes in nine new patients showing homozygosity for perforin gene among a total of 37 (24%) Turkish FHL families studied by linkage analysis (14). Molecular analysis of the family members showed that one of her asymptomatic older sisters, who was 4 years old at the time of the study, also carried the same homozygous change (14). During follow-up of this case, clinical and laboratory findings of FHL developed and HLH 2004 treatment was initiated (15). The patient presented with CNS involvement without systemic findings of FHL 4 months after completion of treatment protocol. Our aim is to emphasize that cases of FHL with homozygosity for perforin gene may be admitted with CNS involvement in the absence of systemic findings.

CASE REPORT

A 7-year-old girl was admitted with the complaints of headache, lethargy and absence of appetite 4 months after completion of HLH treatment. She was diagnosed as HLH 1 year ago, and completed HLH2004 treatment protocol lasting 40 weeks. Pedigree analysis revealed six deceased siblings. Molecular analysis of the family members showed that one of her sisters, who was 3 -year-old, also carried the same homozygous change, died 2 months after the diagnosis. Physical examination revealed lethargy and neck stiffness. …

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